Bacillus anthracis (BA) is a CDC Category A agent. Because of the high mortality due to inhalational anthrax despite antibiotic therapy, new therapeutics are needed. The work proposed focuses on interruption of quorum sensing (QS) as an approach to interfering with BA cell-cell communication. Our preliminary work shows that luxS mutant BA cells do not produce AI-2, and have diminshed growth. Two (2) naturally occuring furanone QS inhibitors and 2 synthetic inhibitors arrest BA growth, and diminish toxin production. The furanones are not inhibitory to macrophages in concentrations that are therapeutically effective. Based on this target (QS) and 4 BA inhibitors, we propose to address their utility as new therapies for anthrax. In Aim 1, we will assess toxicity in both macrophage cell culture and in mice to determine the maximum safe levels that can be used. In Aim 2, we will begin efficacy trials using the Sterne (vaccine) strain 34F2 first in macrophages, then in experimentally challenged mice. Mice will be challenged with LD50 and 10 or 100 x LD50 doses, and we will assess illness and survival based on furanone used, dose, and timing. Ciprofloxacin or daptomycin will be used as comparitors, and synergies with the furanones explored as well. In Aim 3, the lead compound will be tested in a mice model with virulent BA spores in an ABL3 facility. In initial studies, spores will be given subcutaneosly. Efficacy parameters will be defined as above. Successful trials can lead to phase I studies in humans, and treatment studies in non-human primates.